Inhibition of Endoglin Exerts Antitumor Effects through the Regulation of Non-Smad TGF-β Signaling in Angiosarcoma

Sakamoto, Ryoko; Kajihara, Ikko; Miyauchi, Hitomi; Maeda‐Otsuka, Saki; Yamada‐Kanazawa, Saori; Sawamura, Soichiro; Kanemaru, Hisashi; Makino, Katsunari; Aoi, Jun; Makino, Takamitsu; Fukushima, Satoshi; Masuzawa, Mamiko; Masuzawa, Mikio; Amoh, Yasuyuki; Hoshina, Daichi; Abe, Riichiro; Ihn, Hironobu

doi:10.1016/j.jid.2020.01.031

Cited by 10 publications

(8 citation statements)

References 53 publications

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“…It has been reported that TGF-β can activate Smad2 and Smad3 (38). Moreover, Smad4 is known to be a core of TGF-β signaling (39). In this study, we found that LINC01234 knockdown downregulated the expression of p-Smad2, p-Smad3 in liver cancer cells and increased the level of Smad4 in Cytoplasm of Huh-7 cells.…”

Section: Discussionsupporting

confidence: 49%

Knockdown of lncRNA LINC01234 Suppresses the Tumorigenesis of Liver Cancer via Sponging miR-513a-5p

Song

et al. 2020

Front. Oncol.

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Background: Liver cancer is a frequent malignancy with poor prognosis and high mortality all over the world. It has been reported many lncRNAs could modulate the tumorigenesis of liver cancer. To identify novel potential targets for liver cancer, the differential expressed lncRNAs between liver cancer and adjacent normal tissues was analyzed with bioinformatics tool. Methods: The differential expressed lncRNAs between liver cancer and adjacent normal tissues were analyzed with bioinformatics tool. Cell viability and proliferation was tested by CCK8 and Ki67, respectively. Apoptosis of liver cancer cells was tested by flow cytometry. Gene and protein expressions in liver cancer cells were measured by qRT-PCR and western blot, respectively. In vivo model of liver cancer was established to detect the effect of LINC01234 on liver cancer in vivo. Results: LINC01234 was found to be negatively correlated with the survival rate of patients with liver cancer. Moreover, knockdown of LINC01234 significantly suppressed the proliferation and invasion of liver cancer cells via inducing the apoptosis. Meanwhile, miR-513a-5p was sponged by LINC01234, and USP4 was found to be a direct target of miR-513a-5p. In addition, LINC01234 knockdown inhibited the tumorigenesis of liver cancer via inactivating TGF-β signaling. Furthermore, silencing of LINC01234 notably inhibited the tumor growth of liver cancer in vivo. Conclusion: Downregulation of LINC01234 could inhibit the tumorigenesis of liver cancer via mediation of miR-513a-5p/USP4/TGF-β axis. Thus, LINC01234 might serve as a new target for the treatment of liver cancer.

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Section: Discussionsupporting

confidence: 49%

Knockdown of lncRNA LINC01234 Suppresses the Tumorigenesis of Liver Cancer via Sponging miR-513a-5p

Song

et al. 2020

Front. Oncol.

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“…It has been reported that TGF-β can activate Smad2 and Smad3 (38). Moreover, multiple studies have found that Smad4 loss on its own does not initiate tumor formation, but can promote brosis initiated by other genes, such as KRAS activation in pancreatic duct adenocarcinoma and APC inactivation in renal diseases (39). In this study, we found that LINC01234 knockdown downregulated the expression of p-Smad2, p-Smad3 in liver cancer cells.…”

Section: Discussionmentioning

confidence: 47%

Knockdown of lncRNA LINC01234 suppresses the tumorigenesis of liver cancer via sponging miR-513a-5p

Song

et al. 2020

Preprint

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Background: Liver cancer is a frequent malignancy with poor prognosis. It has been reported that many lncRNAs could regulate the progression of liver cancer. To identify potential therapeutic targets for liver cancer, we conducted bioinformatics analysis of lncRNAs in tumor tissues and adjacent normal tissues. Methods: The differential expression of lncRNAs between liver cancer tissues and adjacent normal tissues were examined by bioinformatics analysis. Cell proliferation was tested by CCK-8. Cell apoptosis in liver cancer was detected by flow cytometry. Gene and protein expression in liver cancer cells were measured by q-PCR and Western-blot, respectively. Xenograft tumor model was established to verify the function of LINC01234 on liver cancer in vivo . Results: LINC01234 was found to be notably upregulated in liver cancer tissues. In addition, knockdown of LINC01234 significantly inhibited the proliferation, invasion and induced the apoptosis of liver cancer cells. Meanwhile, miR-513a-5p was a downstream target of LINC01234 and USP4 was a direct target of miR-513a-5p. Moreover, downregulation of LINC01234 inhibited the tumorigenesis of liver cancer via inactivating TGF-β signaling. Conclusion: Downregulation of LINC01234 could inhibit the progression of liver cancer. Thus, LINC01234 may serve as a potential novel target for treatment of liver cancer.

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“…ENG expression has been reported in different human sarcomas, correlating with malignancy, aggressiveness or worse survival (25-29). Here we demonstrate that ENG is highly expressed on both tumor cells and ECs in human MPNSTs and that its expression correlates with advanced stages of the disease (local recurrence and distant metastasis), providing evidence for the use of both tumor and endothelial ENG as markers of MPNSTs transformation.…”

Section: Discussionmentioning

confidence: 99%

Endoglin, a novel biomarker and therapeutical target to prevent malignant peripheral nerve sheath tumor growth and metastasis

González-Muñoz

Giannatale

García‐Silva

et al. 2022

Preprint

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Purpose: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGF-β coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. Experimental Design: ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathways and in vivo MPNST growth and metastasis were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. Results: ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST tumor growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Importantly, combination of anti-ENG therapy with MEK inhibition reduced more effectively tumor cell growth and angiogenesis. Conclusions: Our data unveil a tumor-promoting function of ENG in MPNSTs and support the combined use of anti-ENG antibodies and MEK inhibitors as a novel potential combination to control MPNSTs growth and metastasis.

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Inhibition of Endoglin Exerts Antitumor Effects through the Regulation of Non-Smad TGF-β Signaling in Angiosarcoma

Cited by 10 publications

References 53 publications

Knockdown of lncRNA LINC01234 Suppresses the Tumorigenesis of Liver Cancer via Sponging miR-513a-5p

Knockdown of lncRNA LINC01234 Suppresses the Tumorigenesis of Liver Cancer via Sponging miR-513a-5p

Knockdown of lncRNA LINC01234 suppresses the tumorigenesis of liver cancer via sponging miR-513a-5p

Endoglin, a novel biomarker and therapeutical target to prevent malignant peripheral nerve sheath tumor growth and metastasis

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